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Annual Review of Cancer Biology

Volume 9, 2025

Single-Cell Technologies for Studying the Evolution and Function of Mitochondrial DNA Heteroplasmy in Cancer

  • Sonia Boscenco1,†, Erin M. Cumming2,†, Minsoo Kim1, Caleb Lareau2,* and Ed Reznik1,*
  • 1Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; email: [email protected] 2Computational and Systems Biology Program, Sloan Kettering Institute, New York, NY, USA; email: [email protected]
    * Corresponding authors
    † These authors contributed equally to this article
  • Vol. 9:161-180 (Volume publication date April 2025)
  • First published as a Review in Advance on November 12, 2024
  • Copyright © 2025 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information.

Abstract

The mitochondrial genome, which encodes genes essential for respiration and cellular homeostasis, is the target of abundant and highly diverse somatic alterations in cancers. Somatic alterations to mitochondrial DNA (mtDNA) nearly always arise heteroplasmically, producing heterogeneous ensembles of mtDNA within single cells. Here, we review new insights derived from exponential increases in genomic sequencing data that have uncovered the nature of, selective pressure for, and functional consequences of cancer-associated mtDNA alterations. As many discoveries have been limited by their ability to determine cell-to-cell variation in mtDNA genotype, we describe a new generation of single-cell sequencing approaches that resolve otherwise indeterminate models of mtDNA heteroplasmy. In tandem with novel approaches for mtDNA editing and modeling of mutations, these advances foreshadow the quantitative dissection of dosage-dependent mtDNA phenotypes that underlie both tumor evolution and heterogeneous response to therapies.

Keyword(s): cancer, genomics, mtDNA, single cell
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2025-04-11
2025-06-21
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Single-Cell Technologies for Studying the Evolution and Function of Mitochondrial DNA Heteroplasmy in Cancer
Annual Review of Cancer Biology 9, 161 (2025); https://doi.org/10.1146/annurev-cancerbio-080124-102241
/content/journals/10.1146/annurev-cancerbio-080124-102241
/content/journals/10.1146/annurev-cancerbio-080124-102241
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